Is ANKRA2 p.Ser20Arg (c.60C>A) pathogenic?

ANKRA2 p.Ser20Arg (c.60C>A) is classified Uncertain significance in ANKRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.2071); Ultra-rare (popmax 0.041%, nfe).

How common is ANKRA2 p.Ser20Arg (c.60C>A) in the general population?

ANKRA2 p.Ser20Arg (c.60C>A) is ultra-rare (popmax 0.041%, nfe) (gnomAD).

What do computational predictors say about ANKRA2 p.Ser20Arg (c.60C>A)?

AlphaMissense predicts likely benign (score 0.2071) — an in-silico prediction, not a clinical call.

ANKRA2 p.Ser20Arg

c.60C>A · rs377503728 · VCV2470060

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.041%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2071	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 3.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 222 bp · p 0.84 · regional, not allelic
Overall
CADD	19.95	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.041% European (non-Finnish) · 484/1,179,966 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.0302% 488/1,613,902 alleles · ultra-rare exomes 479/1,461,756 · genomes 9/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.041%	2,438
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,457

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ANKRA2
Protein: p.Ser20Arg
Coding: c.60C>A
MANE Select: NM_023039
dbSNP: rs377503728
Type: single nucleotide variant
Location: chr5:73562822 (GRCh38)
Gene constraint: LOEUF 1.358 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.37 · 9 PDB

Full ANKRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRA2 p.Ala49Thr Uncertain significance ★ ⚠ same type
ANKRA2 p.Asn58Asp Uncertain significance ★ ⚠ same type
ANKRA2 p.Cys237Phe Uncertain significance ★ same type
ANKRA2 p.Cys99Trp Uncertain significance ★ ⚠ same type
ANKRA2 p.Gln297Leu Uncertain significance ★ ⚠ same type
ANKRA2 p.Gln46Arg Uncertain significance ★ ⚠ same type
ANKRA2 p.Glu140Asp Uncertain significance ★ ⚠ same type
ANKRA2 p.Glu199Gln Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ankra2-p-ser20arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown